Chromatin organization dynamics during maturation and pathological hypertrophy of cardiac myocytes

• Applicant: Professor Dr. Ralf Gilsbach
• Subject Area: Pharmacology ; Cardiology, Angiology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 386460455

Genome-wide epigenetic studies highlight the dynamics of epigenetic processes in cardiac myocyte maturation and disease. Remarkably, major changes occur in intergenic, non-coding regions with cis-regulatory properties. The three dimensional organization of chromatin enables interactions of these regions with distal regulatory regions like i.e. promoters. These interactions occur within higher-order chromatin structures. So far, it remains unclear which chromatin structures and interactions occur in cardiac myocytes and how they influence gene expression. Aim of this project is to unravel the dynamics of chromatin structure as well as interactions of promotor regions in mouse cardiac myocytes during fetal and postnatal maturation and heart failure. In addition, we will prove the functional relevance of promotor interactions. To reach this aim, the projects consist of three specific aims. Aim A is to elucidate the chromatin structure of fetal (E14.5), postnatal (P1), adult and failing cardiac myocytes using high-throughput chromosome conformation capture analysis (Hi-C). Aim B is to perform high resolution interaction analysis for more than 2500 differentially regulated genes (promotor-Chi-C), to identify interacting cis-regulatory regions. We will integrate comprehensive epigenetic and gene expression data in the analysis of chromatin structure (aim A) and interactions (aim B). Aim C is to ablate cis-regulatory regions using the CRISPR/Cas-Technology in ES-cell derived cardiac myocytes, to prove their regulatory role.For the first time, this project will provide genome-wide insights into the interplay of chromatin structure and promotor interactions with epigenetic mechanisms and gene expression in cardiac myocytes during maturation and in disease. The identified regulatory mechanisms will provide a basis for the development of novel epigenetic therapeutic concepts.

• DFG Programme: Research Grants